# Taperin-based macromolecular complex at the base of stereocilia

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $672,219

## Abstract

Project Summary
Congenital hearing loss affects about 2 to 3 out of every 1,000 children in the USA. Many genes associated
with congenital deafness encode proteins that are essential for formation of the actin-based
mechanosensory stereocilia in the inner ear hair cells. A number of molecules responsible for growth of
stereocilia and establishing their perfect staircase-like arrangement within a hair bundle have been identified.
However, less is known about the proteins shaping the base of stereocilia. Yet, this is exactly the point,
around which the rod-like stiff stereocilium rotates during sound-induced vibrations. Therefore, the
molecules located at stereocilia base determine both the mechanical properties of the hair bundle (and
hence its overall sensitivity) and its susceptibility to excessive deflections (acoustic trauma). Only in the last
two decades, we and others identified TRIOBP4/5, Fam65b/RIPOR2, and taperin (TPRN) as the proteins
essential for formation of the rootlets of the auditory hair cell stereocilia, shaping stereocilia “taper”, and
determining mechanical properties of the hair bundle. Here, we propose a central hypothesis that, in
addition to the already known distinct actin compartments inside stereocilium - at the very tip (stereocilia
growth), shaft (widening and stiffening), and rootlets (resilient deflections) - there is a distinct compartment
of F-actin that is cross-linked by TPRN at the base of stereocilium. This compartment anchors mechanically
the rootlet and prevents pulling the stereocilium out of cuticular plate. It also controls disassembly of
supernumerary stereocilia during postnatal development. This central hypothesis is well supported by our
preliminary data. We have found that TPRN crosslinks actin filaments in vitro and disrupts stereocilia actin
core when overexpressed in vivo. We have also identified interacting partners of TPRN that form protein
complex at the base of stereocilia. We have generated several mouse models with genomic truncations or
deletions in Tprn gene, including deletion that does not disrupt F-actin crosslinking in vitro. Preliminary
studies revealed structural and functional abnormalities in the auditory hair cell stereocilia of these mice. To
test our hypotheses further, we will: i) determine how exactly TPRN organizes F-actin in vitro; ii) determine
the effects of taperin deficiency on stereocilia F-actin in vivo; iii) elucidate the effects of TPRN deficiency on
mechanical properties of stereocilia bundles; and iv) determine how TPRN-based complex affects normal
disassembly of supernumerary stereocilia in postnatal development. Overall, our study will elucidate the
molecular machinery that shapes stereocilia at their base, thereby determining their optimal mechanical
properties that are essential for normal hearing.

## Key facts

- **NIH application ID:** 10905323
- **Project number:** 2R01DC017147-06
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Gregory I Frolenkov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $672,219
- **Award type:** 2
- **Project period:** 2018-07-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905323

## Citation

> US National Institutes of Health, RePORTER application 10905323, Taperin-based macromolecular complex at the base of stereocilia (2R01DC017147-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10905323. Licensed CC0.

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